Donepezil is a piperidine derivative that is somewhat selective for central AChE. It
reversibly inhibits cholinesterase activity. Donepezil is highly bioavailable and
exhibits a long half-life, allowing it to be given as a single daily dose. It is highly
protein bound, primarily to albumin.
Donepezil may improve cognition, global function, and behavioral symptoms
across all stages (mild, moderate, and severe) of AD. In a multicenter, double-blind,
placebo-controlled trial, subjects with mild to moderately severe AD improved
during a 12-week treatment period.
47 Subjects taking 10 mg of donepezil at bedtime
improved their cognitive function as measured by the Alzheimer’s Disease
Assessment Scale-Cognitive Subscale (ADAS-Cog), and their overall function as
measured by the Clinician’s Interview-Based Impression of Change with caregiver
48,49 A 24-week multicenter, placebo-controlled trial using
dosages of 5 mg/day and 10 mg/day demonstrated similar results. Both 5- and 10-mg
doses were superior to placebo; adverse effects were less common with the 5-mg
50 A long-term, open-label follow-up study to these trials demonstrated that
donepezil effects may persist for almost 3 years.
Interruption or discontinuation of
donepezil treatment was followed by a return of cognition and function to baseline or
Donepezil is indicated also for the severe stage of AD. A 6-month, double-blind,
parallel group, placebo-controlled study in patients with severe AD (MMSE 1–10)
demonstrated an improvement in the Severe Impairment Battery
Alzheimer’s Disease Cooperative Study activities of daily living inventory for
severe AD. The domains that showed a significant improvement versus placebo were
language, praxis, visuospatial, bowel/bladder function, and ability to get dressed.
There were no differences noted in the neuropsychiatric inventory for behavioral
issues associated with dementia.
53 A 23-mg dose of donepezil was approved for
patients in the moderate to severe stages of AD. Small improvements were seen in
the Severe Impairment Battery, and there was no improvement in the CIBIC-Plus
when compared with the 10-mg dose. More than 30% of the high-dose group and
nearly 18% of the low-dose group failed to complete the 24-week trial.
The most common adverse effects of donepezil are associated with cholinergic
activity. They tend to be mild to moderate in nature and resolve with stabilization of
In a 144-week extension trial of donepezil, the most frequently
encountered adverse effects were nausea, diarrhea, and headache.
however, adverse effects were the primary reason for withdrawal from studies, with
an overall dropout rate of 29% in the treatment groups.
Rivastigmine is a carbamate derivative that inhibits both AChE and
butyrylcholinesterase (BChE) activity. BChE provides an alternative pathway for
acetylcholine metabolism. Rivastigmine inhibits the activity of both cholinesterases,
primarily in the central nervous system.
Its AChE inhibition is greater for the G1 as
33 The drug binds to the esteratic sites of the AChE and
BChE molecules and slowly dissociates. Because of this, it is often referred to as a
“pseudoirreversible” inhibitor.
56 Rivastigmine’s biological half-life is approximately
1 hour, but because its slow dissociation extends its activity for at least 10 hours, it
can be dosed twice daily. Rivastigmine is bound approximately 40% to serum
proteins and is metabolized via hydrolysis to renally excreted inactive compounds.
Rivastigmine absorption is nearly complete, but because it undergoes a significant
first-pass effect, the resultant bioavailability is approximately 36%.
In two large clinical trials conducted in patients with mild to moderately severe
AD, rivastigmine improved cognition, the ability to perform daily activities, and
global function over the course of 24 weeks.
In each multicenter, double-blind,
placebo-controlled trial, subjects were randomly assigned to receive placebo or
low-dose (1–4 mg/day) or high-dose (6–12 mg/day) rivastigmine in two divided
doses during a 26-week period. In one study, subjects in both dosage groups
demonstrated statistically significant improvement after 26 weeks on the ADAS-Cog
In the other trial, only those subjects taking 6 to 12 mg/day
57 An open-label extension study that included subjects
from both previous studies found that subjects taking 6 to 12 mg/day of rivastigmine
had significantly better cognitive function after 1 year than did subjects who had
Adverse effects typically include nausea, vomiting, diarrhea, and other cholinergic
55 They are most common when rivastigmine is taken on an empty
stomach or when the dose escalation is too rapid. Headache, dizziness, and fatigue
are also common adverse effects. Increasing the dose by 1.5 mg twice daily at 4-
week intervals increases drug tolerability and reduces the frequency and severity of
GI side effects. Adverse effect severity appears to be less problematic with a
transdermal formulation that delivers 4.6 or 9.5 mg/24 hours, which correspond to 6-
and 12-mg daily doses of the oral formulation.
59 The maintenance dose is generally
9.5 to 13.3/day. In patients with moderate to severe AD, the maintenance dose is 13.3
mg/day. If treatment is interrupted for at least 3 days, the lowest dosing should be
Like other agents used to treat AD, galantamine enhances cholinergic activity by
inhibiting AChE. However, it also stimulates nicotinic receptors (α 7-nicotinic
receptor agonist) at a site distinct from that stimulated by acetylcholine, an action that
does not rely on the presence of acetylcholine. This action is referred to as allosteric
33 Galantamine is rapidly and completely absorbed, reaches peak serum
levels in less than 2 hours, and has a half-life of approximately 5 hours. It exhibits
low protein binding and has a large volume of distribution. Galantamine is
metabolized primarily by cytochrome P-450 (CYP) isoenzymes CYP2D6 and
CYP3A4, and is eliminated in the urine.
Clinical trials have shown galantamine to be effective for the symptomatic
treatment of mild to moderate AD. Doses of 16 and 24 mg/day produced clinically
meaningful improvement in ADAS-Cog and CIBIC-Plus scores during a 5-month,
randomized, placebo-controlled trial.
61 A similar trial conducted in Europe and
Canada that evaluated patients for 6 months used doses of 24 and 32 mg/day. Both
doses were more effective than placebo, but patients in the 32-mg/day group
exhibited more adverse effects.
62 A 6-month, open-label extension trial showed that
patients treated with galantamine 24 mg/day maintained ADAS-Cog scores
throughout the entire 12 months of the study.
As with the other ChEIs, cholinergic effects in the GI tract are the most commonly
encountered adverse effects. Nausea, diarrhea, vomiting, and anorexia were the most
frequent events encountered during clinical trials.
33,45 They were typically present
during the dose escalation phases of the studies. A dose titration interval of 4 weeks
reduces the severity of adverse effects and increases tolerability.
how should therapy be monitored?
T.D. is in the mild stage of the disease, so a ChEI is an appropriate choice.
unlikely that a ChEI will produce a dramatic or long-lasting improvement in T.D.’s
cognitive abilities. Systematic reviews of ChEI therapy have consistently concluded
that these agents provide modest benefits, at best, in the majority of patients.
Treatment, however, may slow his cognitive decline, help maintain his ability to care
for himself for 1 year or more, and reduce the risk for nursing facility placement for
60 Beneficial effects may occur for as long as 3 years, and patients
who start therapy earlier may experience greater benefit than those who delay
61,62 The choice of drug is based on the agent most likely to produce a
positive response with the fewest adverse effects. Ease of adherence must also be
considered. All agents exhibit similar adverse effect profiles. Rivastigmine may be
less prone to drug interactions because of its metabolic pathway.
as a transdermal patch that is applied daily. Whereas the oral formulation of
rivastigmine requires an initial, nontherapeutic titration dose to reduce the severity of
adverse effects, the initial transdermal dosage is therapeutic.
galantamine extended-release can be given as a single daily dose and are available
as generic equivalents. They can be given at bedtime, which may make cholinergic
side effects less troublesome.
Donepezil may be an appropriate agent for T.D.. He should receive donepezil 5
mg at bedtime. He should be monitored for cholinergic side effects (particularly
nausea and diarrhea), insomnia, headache, and dizziness, the adverse effects most
commonly reported in clinical trials.
47,50 Additionally, he should be monitored for
bradycardia due to his pre-existing low heart rate. Patients who received moderate to
high doses of donepezil showed an increased incidence and greater risk of
bradycardia especially those with risk factors (e.g. cardiovascular disease,
concomitant use of beta blockers, calcium channel blockers, antiarrhythmics).
family and physician should look for improvements in his memory, orientation, and
ability to concentrate on complex tasks, such as managing finances. He may also
CASE 108-1, QUESTION 7: T.D. was unable to tolerate the donepezil and his family was wondering what
other options could be employed to address the progression of the dementia?
After 1 month, his physician should assess him for adverse effects.
improved noticeably after 4 to 6 weeks, the dose of donepezil may be increased to 10
mg at bedtime. If his condition does not respond to donepezil after a 6-month trial, or
he is unable to tolerate the donepezil, it is reasonable to switch T.D. to another ChEI.
Both rivastigmine and galantamine have additional mechanisms of action that might
prove beneficial. Rivastigmine is started at a dose of 1.5 mg twice daily with meals
to slow absorption and improve tolerability. The dose may be increased at 4 week
intervals by 1.5 mg twice daily, up to the maximal dose of 6 mg twice daily;
however, the transdermal formulation is better tolerated and may be preferable by
avoiding a titration phase. Galantamine can be started at 4 mg twice daily or 8 mg
daily (extended-release) and increased every 4 weeks by 8 mg, up to a maximal dose
of 24 mg daily. As with oral rivastigmine, the initial dose is not therapeutic.
galantamine with meals may improve tolerability of GI effects. If a trial of a second
agent does not improve or stabilize a patient’s condition, there is no value in
attempting a third agent. T.D. should have routine reassessment of his daily function,
cognition, and behavior at 6-month intervals.
65-67 Close attention also must be paid to
his other medical conditions, and his family should be provided ongoing support,
such as through an AD caregiver support group.
As T.D.’s AD progresses, there are two treatment options that can be tried. One
option is to further titrate up the donepezil dose to 23 mg a day as mentioned above
with some limited clinical efficacy.
glutamate in the central nervous system that can lead to excitotoxic reactions and cell
death in AD and other neurodegenerative disorders.
68 Memantine is a noncompetitive
NMDA receptor antagonist with moderate affinity and voltage-dependent binding. It
is completely absorbed after oral administration, reaches peak serum concentrations
in 3 to 8 hours, and is moderately protein bound.
Multiple clinical trials have evaluated memantine in subjects with moderate to
severe AD. A dose of 10 mg/day for 12 weeks increased functional ability (e.g.,
dressing, toileting, participating in group activities) and reduced care dependence
68 A 28-week trial using a dose of 20 mg/day improved
CIBIC-Plus scores, activities of daily living, and global function compared with
69 Overall, the benefits of memantine are modest.
memantine and a ChEI has been shown to be superior to a ChEI alone by improving
daily function in individuals with moderate to severe dementia.
effects include diarrhea, insomnia, dizziness, headache, and hallucinations.
Memantine has also been studied in patients with mild to moderate AD with 2,000
IU/d of alpha tocopherol compared with placebo.
74 The alpha tocopherol resulted in
slower functional decline, while there were no significant differences in the groups
receiving memantine alone or memantine plus alpha tocopherol. T.D. should be
started on memantine 5 mg daily, with the dosage increased in weekly intervals by 5
mg/day, up to a dose of 10 mg twice daily.
68 As an alternative, he can be started on
the extended-release formulation given in weekly escalating doses of 7, 14, 21, and
Lewy bodies are hyaline-containing inclusion bodies typically found in people with
Parkinson’s disease. Recently, attention has been given to distinguish DLB and PDD
It is known that up to 25% of patients with dementia have
Lewy bodies in the brainstem and cortex (particularly in the limbic and paralimbic
cortices and frontal and temporal lobes).
5,76 Concentrations are found in the
substantia nigra, locus coeruleus, hypothalamus, basal nucleus of Meynert, and
neocortex. There is decreased dopamine in the basal ganglia and a loss of choline
acetyltransferase (and thus, acetylcholine) in the basal nucleus of Meynert.
these patients display extrapyramidal signs without the classic presentation of
7 The role of α-synuclein is a common biological theme in both
DLB and PDD, with α-synuclein aggregates found in Lewy bodies and neurites.
through the house trying to steal anything that can be hidden in a coat pocket.”
Given her physical health, inability to live alone because of impaired cognition,
and MMSE score, J.F. meets the criteria for dementia. Her rigidity, bradykinesia, and
masked facies are consistent with early Parkinson’s disease (see Chapter 59
Parkinson’s Disease and Other Movement Disorders). There have been revised
criteria for the clinical diagnosis of DLB (Table 108-1).
77 J.F. exhibits all the central
features, two core features, and the supportive feature of repeated falls. Her
presentation is consistent with probable DLB versus PDD because of her temporal
sequence and lack of well-established diagnosis of Parkinson’s disease.
CASE 108-2, QUESTION 2: What is an appropriate treatment for J.F.?
To date, ChEIs are the only treatment strategy for the cognitive symptoms of both
PDD and DLB. All ChEIs have demonstrated symptomatic benefit in patients with
78,79 The largest randomized, placebo-controlled trials have used rivastigmine
(up to 12 mg/day) in subjects with mild to moderate disease, and this medication has
received US Food and Drug Administration (FDA) indication for PDD. Rivastigmine
was reported to worsen tremor in 10% of the patients with PDD, yet overall there
was not a statistically significant difference between groups.
treatment has demonstrated improvements in apathy, anxiety, delusions, and
hallucinations when titrated appropriately to doses of 6 to 12 mg daily.
initiation, titration, and monitoring are conducted in the same manner as when ChEIs
are used for the treatment of AD.
J.F.’s symptoms of Parkinson’s disease should be fully evaluated, and appropriate
treatment, such as levodopa/carbidopa, should be started (see Chapter 59,
Parkinson’s Disease and Other Movement Disorders). Because several medications
for parkinsonism can have psychiatric effects, it is important to monitor for adverse
effects such as worsening psychosis and cognition. Typical antipsychotics, such as
haloperidol, may worsen her extrapyramidal symptoms (EPS) and should be
avoided. Novel atypicals, namely, quetiapine and clozapine, may be less likely to
exacerbate the parkinsonism but should be instituted after a trial of a ChEI or if more
acute symptom control of behaviors is required.
VaD is a broad classification of cognitive disorders caused by vascular disease. The
most common cause of VaD is occlusion of cerebral blood vessels by a thrombus or
embolus, leading to ischemic brain injury.
In the majority of cases, the dementia
syndrome is the result of multiple individual cerebral infarcts, a single infarct in an
area related to cognitive function, or diffuse white matter lesions in the subcortex.
A number of diseases, including atherosclerosis, arteriosclerosis, and vasculitis,
lead to the production of emboli and thrombi that potentially occlude brain vessels.
Hemorrhagic phenomena and disorders such as hypertension or cardiac disease can
produce episodes of cerebral ischemia or hypoxia and are responsible for some
81-83 Specific risk factors for VaDs include advancing age, diabetes
mellitus, small vessel cerebrovascular disease, hypertension, heart disease,
hyperlipidemia, cigarette smoking, and alcohol use.
VaDs are typically subcortical. Most patients with VaD have blockage of multiple
blood vessels and infarction of the cerebral tissue supplied by those vessels.
When the distribution of a large artery or medium-size arteriole is blocked, focal
neurologic deficits can result (see Chapter 61, Ischemic and Hemorrhagic Stroke).
Depending on the area affected, there may be significant cognitive impairment. More
often, however, a patient may have experienced transient ischemic attacks (TIAs) or
multiple microinfarcts that have remained unrecognized.
83,84 Patients with subcortical
VaDs often exhibit small, deep ischemic infarcts in arterioles of the basal ganglia,
thalamus, and internal capsule.
83,84 A history of atherosclerosis, diabetes mellitus, or
hypertension is often present without a history of stroke.
useful in diagnosing VaDs because areas of cerebral infarction are easier to visualize
than they are with CT scanning (Fig. 108-3).
16,22 Lesions in white matter may occur in
as many as 85% of patients with VaD. Deep white matter lesions known as
leukoaraiosis often include demyelination and may represent early changes in
83 Because of the etiologic factors involved, VaD typically has an earlier
onset than AD, and affects more men than women.
that the impairment began approximately 1 year before that episode. The memory loss has been slowly
half a pack of cigarettes per day. His medical history is unremarkable except for the possible TIAs,
basal ganglion lacunar infarcts, and small cortical infarcts in the right parietal lobe.
What subjective and objective evidence exists for a diagnosis of dementia in D.V.?
D.V.’s major complaint is “fuzzy thinking” and impaired memory that he attributes
to his dizzy spell and fall. However, his family began to note problems a full year
before that episode, with progression over time. Although D.V. denies that his
impairment significantly affects his daily routine, he has voluntarily stopped driving
and relies on his daughter for assistance with financial matters. His memory
difficulties appear to have affected his mood and made him feel useless. D.V. is
disoriented at night when he awakens to urinate. These factors satisfy the DSM-V
criteria for interference with normal activities.
Multiple deficits are present on both the Folstein MMSE
wheel of a car; a disturbance of higher cortical function is indicated by his need for
assistance with financial matters. There is no evidence of a delirium being present.
Evidence of an organic cause is provided by the MRI scan.
CASE 108-3, QUESTION 2: What type of dementia does D.V. have?
There is sufficient evidence to indicate that D.V. suffers from a neurocognitive
disorder. DSM-V provides diagnostic criteria for VaD ( Table 108-1) and it appears
that the history and findings satisfies the possible VaD (unclear of temporal
relationship between TIAs and decline).
1 VaDs commonly present suddenly after a
cerebrovascular insult. This is followed by a period of stability and further declines
after additional episodes, often in a stepwise pattern. Cognitive impairments are
variable and depend on the area of the brain affected by the insult.
With the exception of the dizzy spell and fall, D.V.’s deterioration has had a
pattern that resembles a downhill slide rather than stepwise decline. Although his
cognitive deficits are “patchy” (e.g., he appears to have no language difficulty), they
are not particularly prominent. D.V. displays some neurologic signs and symptoms,
including diminished extraocular movements, asymmetric reflexes, and a mild
shuffling gait, but they are subtle and might be easily missed by an untrained observer
as being related to a dementia. Reliance solely on the clear presence of diagnostic
criteria may often lead to a missed diagnosis.
22 The Hachinski Ischemic Scale ranks
signs and symptoms associated with cognitive impairment of cerebrovascular origin
and is used to help differentiate between AD and VaD.
D.V.’s nocturnal confusion, depression, hypertension history, and focal neurologic
signs and symptoms are sufficient to indicate VaD.
D.V.’s history and clinical presentation do not suggest dementia caused by a single
large stroke or several small strokes. Large strokes produce significant motor
damage, typically on one side of the body (the side contralateral to the stroke).
Multiple smaller strokes cause prominent motor deficits in discrete areas controlled
by the affected areas. Neither of these patterns describes D.V.’s condition. However,
he is clearly exhibiting signs of dementia and has significant cerebrovascular
disease. He possesses several risk factors for a VaD, including hypertension,
smoking, and hyperlipidemia. His MRI indicates a lacunar state, with multiple small
infarcts in the deep penetrating arterioles at the base of the brain, particularly in the
basal ganglia, internal capsule, thalamus, and pons (see Chapter 61, Ischemic and
Hemorrhagic Stroke). These MRI findings are consistent with D.V.’s long-standing
hypertension and neurologic presentation.
CASE 108-3, QUESTION 3: How should D.V. be managed?
Several treatment options that modify risk factors for VaDs are available.
D.V. should be counseled to stop smoking because cigarette smoking reduces
cerebral blood flow and increases the risk for stroke. Among smokers with VaD,
cessation of cigarette use improves cognitive performance.
Hypertension and hyperlipidemia, both present in D.V., are additional risk factors for
stroke and VaD. Control of systolic hypertension reduces the risk of stroke by 36% in
87 and maintaining the systolic BP between 135 and 150 mm Hg is
associated with improved cognition among MID patients. A systolic BP that exceeds
150 mm Hg indicates inadequate control, whereas a systolic BP less than 135 mm Hg
may lead to inadequate cerebral perfusion.
The antihypertensive agent must be chosen carefully in this population to maximize
compliance and minimize adverse reactions.
cognitive activity. Calcium-channel blockers or angiotensin-converting enzyme
inhibitors are acceptable because they are well tolerated by elderly patients and may
help preserve renal function in patients with diabetes mellitus (see Chapter 9,
Dihydropyridine calcium-channel blockers have been shown to improve cognition
in patients with dementia and reduce the risk of dementia in elderly patients with
isolated systolic hypertension.
90 Because D.V. has benign prostatic hyperplasia, he
may benefit from the use of an α-adrenergic blocking agent, such as doxazosin 1 mg at
bedtime or terazosin 1 mg at bedtime (see Chapter 109, Geriatric Urologic
Disorders). Evidence indicating an increased risk for negative cardiac outcomes,
however, makes the α-adrenergic blocking agents less attractive choices.
a vasodilating calcium-channel blocker, such as amlodipine 5 mg once daily, is an
appropriate first choice. An angiotensin-converting enzyme inhibitor such as
benazepril 10 mg once daily is an appropriate alternative. Both agents exhibit the
advantage of once-daily dosing over some other agents within their respective
classes. This feature is important for maximizing adherence in patients with declining
Prophylaxis against future cerebrovascular events is indicated in VaD, but few
studies that have looked specifically at individuals with dementia are available.
Cerebral perfusion and cognitive performance were improved in VaD patients
receiving aspirin 325 mg/day for 1 year when compared with a control population.
Guidelines from the American Heart Association and the American Stroke
Association recommend the use of antiplatelet therapy in patients with a history of
TIA or atherothrombotic stroke that is not of cardiogenic origin. Aspirin in doses of
50 to 325 mg/day, clopidogrel 75 mg daily, or aspirin 50 mg/dipyridamole 200 mg
twice daily are all effective treatments for stroke prophylaxis.
possibly targeted specific oral anticoagulant (TSOACs) may be recommended after
cardioembolic cerebral ischemic events. However, only aspirin has been studied
specifically in VaD patients. Aspirin 81 to 325 mg daily is an appropriate first
Deficits in cholinergic transmission and nicotinic receptor binding abnormalities
5,94 Early clinical trials with donepezil,
97 have demonstrated improvement in cognition and daily function among
patients with VaD. As of yet, however, the use of these agents remains investigational
and controversial. Because the use of these agents is not FDA-approved for VaD,
D.V. and his family should have a thorough discussion with his physician regarding
the potential risks and benefits when considering ChEI treatment for him.
D.V. should be referred for physical and occupational therapy for an assessment of
his strength, gait, and daily function. Physical therapy can help him maintain his
strength. Occupational therapy can provide him with equipment and strategies to
adapt to his dizziness and avoid falls. In addition, the use of reminder notes and
labels around the house will assist him in maintaining his independence.
BEHAVIORAL DISTURBANCES IN DEMENTIA
Several types of behavioral disturbances may develop during the course of a
dementia and occur in almost all patients, particularly during the later stages (Table
38,41 Behavior symptoms include a wide range of disturbances, including
agitation, apathy, wandering, verbal and physical aggression, and psychotic
41 Agitation in dementia has been described as excessive motor activity
with a feeling of inner tension that may lead to related symptoms such as anxiety,
irritability, motor restlessness, and abnormal vocalization.
mood disorders, such as anxiety and depression, also are common.
anxiety are often managed best with nonpharmacologic treatment. Pharmacologic
interventions are appropriate when nondrug therapies are unsuccessful or the
behavior is severe. Non-psychologic behaviors such as wandering and inappropriate
motor activity respond better to environmental modification than to drug therapy.
The first step in evaluating altered behavior in patients with dementia is to ensure
that the problem is not the result of an unrecognized medical problem (e.g. pain),
environmental factors or caused by an adverse effect of a medication (see Chapter
urinate. His concerns contribute to his nighttime awakenings, making him quite tired during the day.
How should T.G.’s agitation and anxiety be managed?
Anxiety and unfocused activity are common problems in the early stages of
dementia. Agitation is a general term that, while commonly used, is subject to wide
interpretation. It typically is
used to describe specific behaviors such as restlessness, irritability, or unfocused
motor activities. Patients are aware of their progressive cognitive decline and have
sufficient insight to understand the consequences. T.G.’s shadowing of his wife
indicate insecurity and anxiety; pacing through the house is an example of
restlessness and unfocused behavior. T.G. is exhibiting anxiety, as evidenced by his
worry about placing a burden on his family. His poor sleep is attributable to both
If T.G.’s behavior represents a sudden or rapid change, his physician should first
evaluate him for a medical condition such as infection, pain, or a medication-related
problem. Although T.G. has been taking hydrochlorothiazide without difficulty, he
may no longer be recognizing the cues to urinate. The drug should be discontinued; if
his blood pressure rises, the amlodipine dose can be increased. This may help with
his incontinence, nocturia, and disturbed sleep.
threatened several members of the family recently. How should T.G.’s paranoid behavior be managed?
Once medical problems have been ruled out or corrected, he should be evaluated
using a systematic approach, as behavior problems are part of a chain of events. T.G.
may be described as “agitated,” but his behavior is shadowing his wife and pacing
through the house. The behavior has an antecedent; because he has a dementia, he
may be unable to initiate a meaningful or enjoyable activity on his own, and
consequently he becomes bored. The consequence of his boredom is that he annoys
his wife and paces the house. This represents what often is termed an “A-B-C”
approach, for antecedent, behavior, consequence.
99 Pacing is a demonstration of
unfocused energy. T.G.’s wife can give him simple tasks to perform, such as drying
dishes, folding laundry, or simple gardening, to help channel his energy. It also may
relieve his anxiety and insecurity. She also could accompany him on walks to
alleviate his fear of getting lost. She may want to consider enrolling him in an adult
day-care program. This would give him meaningful activity that might help him use
up his excess energy and sleep better at night. It also will provide her with some
respite and avoid or delay caregiver burnout. Appropriate strategies to manage
agitated behaviors without medication are listed in Table 108-6.
When non-pharmacologic interventions are not successful in reducing anxiety,
irritability, and similar behaviors, medications can be considered. Benzodiazepines
are the most commonly used anxiolytics and will address T.G.’s insomnia and
anxiety. However, they are associated with several negative outcomes in the elderly,
including confusion, amnestic syndromes, ataxia, and falls.
addition to other medications, may be considered potentially inappropriate
medications in older adults as described in the 2015 American Geriatrics Society
Beers Criteria. If a benzodiazepine is clinically warranted, agents such as lorazepam
or oxazepam, may be used, if necessary, but only for a short term and with caution.
Trazodone is a sedative antidepressant that is effective for insomnia and agitated
behaviors in patients with AD.
101,103 Treatment is started at 25 mg at bedtime and may
be increased to a dose of 250 mg/day in divided doses. Another alternative treatment
is buspirone, which does not cause the cognitive impairments associated with the
benzodiazepines. Dosage begins at 5 mg three times daily and may be increased up to
15 mg three times daily. However, buspirone will not concurrently manage T.G.’s
insomnia because it has no sedative effect, and there is no reliable evidence that it is
efficacious in anxiety associated with dementia.
102 Citalopram has been shown to
reduce agitated behaviors in people with dementia and could be used.
evidence suggests that dextromethorphan-quinidine combination may be efficacious
in reducing agitation but caution exists in light of drug-drug interactions as well as
If the nondrug strategies are ineffective in reducing T.G.’s insomnia and agitation,
trazodone should be initiated at a dose of 25 mg at bedtime. It may be increased by
25 mg/day at 5- to 7-day intervals, up to 100 mg. Doses above 100 mg/day should be
Delusions and hallucinations are common among individuals with dementia.
Paranoid symptoms, often accompanied by aggression, have been reported in more
than half of dementia patients.
103 Delusions typically involve suspicion of theft by
family members, which may be secondary to the patient’s inability to remember
where valuable items were placed and incorrectly concluding that they were
106 Another common delusion is the misidentification of people or objects.
individuals, may occur in almost half of demented individuals.
There are a few behavioral interventions that could be tried first before resorting
to medications, which produce limited benefits and are accompanied by significant
108,109 The first step is to conduct a person-centered examination of the symptoms.
Several questions need to be answered. What is the significance or meaning of these
behaviors to T.G? (For example, he cannot locate items that are valuable to him, and
does not recall where they are.) What triggers his thoughts and outbursts? (He may
assume the items were stolen, and believes that his family, knowing their location,
has taken them for their own gain.) How is the family’s response further angering
him? (If the family searches for and finds the items, it may reinforce his delusion that
they stole them.) The family should be educated that paranoid behavior is common in
dementia, and that it is likely to pass as the disease progresses. Depending on how
fixed the paranoia is, distraction or redirection, such as changing the subject to
something more pleasant, or initiating a pleasant activity, could resolve the problem.
Regardless of the strategy, they need to be taught not to argue or debate with T.G. but
to share his concern. When these strategies fail, then, depending on severity, it may
be necessary to resort to medication.
Paranoid symptoms respond best to antipsychotic agents, although these are not
highly effective, and no single antipsychotic is more effective than any other.
Delusions, hallucinations, aggression, and uncooperativeness symptoms respond
best, but overall improvement occurs in only a minority of patients.
of psychosis, aggression, and agitation for up to 36 weeks in patient with AD.
Improvement was noted in 32%, 26%, 29%, and 21%, respectively. The authors
concluded that efficacy of the agents was offset by adverse effects.
antipsychotic medications that are approved by the FDA for use in the management of
behavior symptoms in people with dementia. Black-box warnings are present for all
agents because of the increased risk for stroke and mortality when used in this
108,110,111 Consequently, any use of these drugs in a person with dementia is
for an unapproved use and requires a full discussion between the physician, patient,
Behavior Disturbances in Dementia
Anxiety Excessive worrying, sleep
Engage in enjoyable activities
Depression Withdrawal, loss of appetite,
irritability, restlessness, sleep
Engage in meaningful activities
Repeated questions, wandering,
hallucinations, misperceptions
excessive yelling and screaming,
Identify the precipitating cause
Focus on the patient’s feelings
Maintain a simple, pleasant, and
Use music, exercise, etc., as a
Adapted from California Workgroup on Guidelines for Alzheimer’s Disease Management. Guideline for
Kales et al. Assessment and management of behavioral and psychological symptoms of dementia. BMJ.
Alzheimer disease: a randomized controlled trial. JAMA. 2003;290:2015.
The risks and potential benefits of therapy must be carefully weighed for T.G.
before determining the appropriate treatment. The choice of an antipsychotic agent is
determined by the symptoms displayed by the patient as well as the potential for
adverse effects. T.G. is experiencing a delusion of theft, suspiciousness, and
aggressive behavior. It is possible that the verbal abuse and threats are consequences
of fear brought on by the false belief that his family is stealing from him and plans to
T.G. has no major contraindications to the use of any antipsychotic agent, and his
target symptoms will probably respond to any of the available agents. Therefore, a
therapeutic trial is appropriate. The choice can be made according to which
antipsychotic agent is least likely to cause intolerable adverse effects. Risperidone
has been evaluated in a case series and in a large double-blind, placebo-controlled
In the case study series, symptoms improved in half of the patients taking
dosages ranging from 0.5 mg every other day to 3 mg twice daily. However, 50%
also experienced EPS, even at the lowest dosage used.
mg/day, or 2 mg/day for 12 weeks. Daily doses of 1 or 2 mg reduced psychosis and
improved behavior, but EPS and somnolence were common adverse effects.
doses of olanzapine, 5 to 15 mg/day, were superior to placebo for reducing agitation,
aggression, and psychosis during a 6-week study among nursing facility residents.
Somnolence and gait disturbances were the most common adverse effects. Quetiapine
has been shown to reduce agitated and psychotic behaviors at doses of 100 to 200
115 Clozapine poses significant risk for hematologic toxicity and requires
careful monitoring. Because T.G. does not have cardiovascular or cerebrovascular
risk factors and does not have gait or balance problems, either risperidone 0.25 mg at
bedtime or quetiapine 25 mg at bedtime can be initiated. Doses of risperidone may
be increased by 0.25 mg/day in weekly intervals, up to 2 mg/day; quetiapine doses
can be increased by 25 mg/day, up to 200 mg/day in divided doses. Once his
behavior has stabilized, the medication should be continued for about 3
months. At that time, the dose should be decreased in weekly intervals to
determine whether the medication is still required. T.G. should be monitored closely
for adverse effects, including EPS, which can occur with the atypical
Although psychotic symptoms respond to antipsychotic agents, many other
behaviors do not. Up to 90% of patients with dementia exhibit at least one disruptive
behavior such as angry outbursts, screaming, and abusive language, and many display
multiple aggressive behaviors.
110 As many as 32% exhibit moderate to severe
110 Such behaviors are typically directed at caregivers, precipitated by
receipt of assistance with activities of daily living such as bathing and toileting, and
increase in frequency with dementia severity.
99,117 Several of these behaviors may be
merely defensive responses to perceived threats in cognitively impaired
117 Behavioral disturbances must be addressed because they can have a
negative effect on the patient’s ability to perform activities of daily living.
Some behaviors exhibited by T.G. are not likely to respond to medications.
Wandering is typically unaltered by the use of medications unless the patient is
oversedated. Non-pharmacologic treatments, such as periods of physical exercise
and rest, or environmental modification is much more effective.
reactions to assistance with bathing and toileting may be caused by confusion and
fear. Breaking the tasks down to step-by-step procedures, accomplished individually,
often helps modify aggressive behaviors.
Verbal abuse and aggressiveness place both the patient and the caregiver at risk
for injury, and may lead to abuse. In these situations, the patient and the caregiver
may each be a precipitator or a target of abuse.
anticonvulsant agents have been shown to reduce rage and aggressive behaviors in
patients resistant to treatment with antipsychotics. Carbamazepine and valproic acid
(including divalproex) are the most well-studied agents.
110,116 Although initial trials
were promising, later studies did not establish efficacy. The lack of benefit plus
concerns about toxicities with each agent have led to recommendations that these
95,109 The addition of an antidepressant medication may be helpful,
as described below. Wandering typically does not respond to pharmacologic
intervention. Appropriate strategies include environmental modification, such as
placing child-safety locks on exit doors; providing activities and other distractions;
and having a safety plan, such as the Safe Return program. As described for his
paranoid behavior, a person-centered evaluation using the A-B-C approach should
be conducted to determine the cause and effects of his aggressiveness. If T.G.’s
aggressive behaviors continue, his family may need to consider obtaining in-home
assistance or placement in an assisted-living facility designed for the care of patients
CASE 108-4, QUESTION 4: How should T.G.’s social withdrawal and apathy be treated?
Depression often accompanies dementia and may significantly impair a patient’s
functional capacity, cognitive abilities, and communication.
and apathetic, symptoms suggestive of depression. Screaming and irritability may be
considered symptoms of depression in individuals with dementia, perhaps reflecting
feelings of loneliness, boredom, or the need for attention.
diagnosis of depression relies heavily on a patient interview and response to
questions, a formal diagnosis in patients with dementia is difficult. Therefore, patient
observation is an important component for making a clinical evaluation. It is possible
that he is reacting to a sense of loss of not only his memory and function, but also a
loss of self. He also may feel isolated by the inability to communicate with others or
participate in the outside world. Helping him to engage in meaningful activities and
social engagement, perhaps as simple as going on a walk or attending adult day care,
may help alleviate his apathy and reverse his withdrawal. Such a strategy is
appropriate to try before considering an antidepressant.
The selective serotonin reuptake inhibitors have not been well studied in patients
with dementia, but are effective antidepressants with adverse effects that are better
tolerated than those of the tricyclic antidepressants. Sertraline, in doses of 50 to 150
mg/day, was superior to placebo in reducing depression in AD patients during a 12-
121 Citalopram has also demonstrated effectiveness; in contrast, fluoxetine
and fluvoxamine have not demonstrated benefit.
104,110 Either sertraline 50 mg daily or
citalopram 10 mg daily are reasonable choices to treat T.G.’s symptoms of
depression if he does not respond to nonpharmacologic strategies. He should be
reassessed in 1 month; if he has not responded, the dose may be increased. Dosages
may be increased weekly up to a maximum of 150 mg/day or 20 mg/day,
respectively. A full therapeutic trial requires a minimum of 3 months.
CASE 108-4, QUESTION 5: T.G.’s family indicates that caring for him at home has become so burdensome
Institutionalization is a typical outcome for patients in the late stages of dementia.
The total care required to manage a dementia patient usually becomes unmanageable
for most families as the disease progresses. Caregiver stress is often exacerbated by
the patient’s declining memory, inability to communicate, physical decline, and
incontinence, as well as the caregiver’s loss of freedom and depression. Caregivers
commonly experience anger, helplessness, guilt, and worry, and suffer from physical
stressors such as fatigue and illness.
Outside assistance is essential to families caring for a patient with dementia.
Families should be referred to the Alzheimer’s Association as soon as a diagnosis of
dementia is received. The association has local affiliates in most major cities. The
book The 36-Hour Day is a valuable resource for families as well.
symptoms, behaviors, and problems that can be encountered when caring for a patient
Support groups, individual and family counseling, and other sources of support are
useful and may help families cope for a longer period. However, the key intervention
to reduce caregiver stress is respite care, which allows a family time away from the
responsibilities of taking care of a frail individual. Respite care brings a person into
the home or allows the patient to go to a day-care center or similar environment on a
regular schedule. Such programs may delay the need to institutionalize a
A full list of references for this chapter can be found at
http://thepoint.lww.com/AT11e. Below are the key references and websites for this
chapter, with the corresponding reference number in this chapter found in parentheses
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Herrmann N et al. Pharmacologic management of neuropsychiatric symptoms of Alzheimer disease. Can J
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Mace NL et al. The 36-Hour Day: A Family Guide to Caring for People with Alzheimer Disease, Other
Alzheimer’s Association. http://www.alz.org
MedicAlert + Alzheimer’s Association Safe Return.
http://www.alz.org/safetycenter/we_can_help_safety_medicalert_safereturn.asp
Advancing Excellence Nursing Home Quality Campaign.
https://www.nhqualitycampaign.org/dementiaCare.aspx
National Institute on Aging. Alzheimer’s Disease Education and Referral Center (ADEAR).
http://www.niapublications.org/adear.
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Urinary incontinence is a common condition in older adults and can be
classified as acute or persistent. Persistent incontinence can further be
classified as urge, stress, overflow, or functional.
Urge incontinence is managed with nonpharmacologic interventions,
such as a toileting schedule, and the use of anticholinergic medications.
Stress incontinence is managed with local estrogens, tricyclic
antidepressants, and duloxetine.
Benign prostatic hyperplasia (BPH) is the most common urologic
condition in aging men. A wide range of signs and symptoms occurs in
BPH that causes patients to seek care.
Management of BPH includes the use of α1A-adrenergic receptor
antagonists and 5α-reductase inhibitors, either alone or in combination.
Nonpharmacologic treatment and surgery may also be considered for
some patients. In general, the use of over-the-counter medications
should not be used to treat symptomatic BPH.
Erectile dysfunction (ED) is a condition that can be a result of
neurogenic, hormonal, or vascular disorders. It is therefore essential that
a complete urologic workup is conducted to assess the underlying
pathophysiology. Underlying conditions should be addressed and treated
before symptomatic therapy is initiated.
Treatment for ED consists of a variety of pharmacologic agents, which
include phosphodiesterase inhibitors, intracavernous injections, and
Neurophysiologic Considerations
The bladder can be thought of as a “balloon” with a narrow outlet, wrapped with a
muscular layer, the detrusor muscle. The detrusor and the bladder outlet functions are
coordinated neurologically to allow for storage and expulsion of urine.
muscle is innervated by the parasympathetic nervous system, and the bladder neck is
innervated by the sympathetic nervous system (α-adrenergic) (Fig. 109-1). The
proximal smooth muscle (internal) sphincter in the bladder neck also is innervated
through the sympathetic nervous system (α-adrenergic). The distal striated muscle
(external) sphincter of the urethra is supplied by the somatic nervous system.
Urine storage is the result of detrusor muscle relaxation and closure of both the
internal and external sphincters. Detrusor relaxation is accomplished by central
nervous system (CNS) inhibition of the parasympathetic tone; sphincter closure is
mediated by a reflex increase in α-adrenergic and somatic activity. Voiding occurs
when detrusor contraction is coordinated with sphincter relaxation. Detrusor
contraction is mediated by the parasympathetic nervous system, and relaxation
requires inhibition of somatic and sympathetic nerve impulses to the outlet. The
bladder capacity is ~300 mL in the elderly and ~400 mL in young adults. The
relationship between the detrusor and the outlet is coordinated by a micturition center
located in the CNS, perhaps in the pons.
2 The cortex and diencephalon also permit
inhibition of what would otherwise be a reflex contraction of the detrusor muscle in
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